Intra-articular injection of synthetic microRNA-210 accelerates avascular meniscal healing in rat medial meniscal injured model

Abstract

IntroductionThe important functions of the meniscus are shock absorption, passive stabilization and load transmission of the knee. Because of the avascularity of two-thirds of the meniscal center region, the treatment of tears in this area is hard. Recently, microRNAs have been proven to play an important role in the pathogenesis of diseases. We focused on microRNA (miR)-210, which plays a wide spectrum of roles comprising mitochondrial metabolism, angiogenesis, DNA repair and cell survival. This study aimed to investigate the effect of intra-articular injection of synthetic miR-210 on the injured meniscus in the avascular zone.MethodsThe middle segments of the medial meniscus of Spraque Dawley rats were incised longitudinally with a scalpel. An intra-articular injection of double-stranded (ds) miR-210 (for control group using control dsRNA) with atelocollagen was administered immediately after injury. Four weeks and 12 weeks after the injection, we conducted a histologic evaluation, immunohistochemical evaluation and Real-time PCR analysis. In vitro, the inner meniscus and synovial cells were isolated from rat knee joint, and were transfected with ds miR-210 or control dsRNA. Real-time PCR and immunohistochemical evaluations were performed.ResultsTwenty-four hours after the injection, FAM (Fluorescein amidite) labeled miR-210 was observed in the cells around the injured site. Four weeks after the injection, the injured site of the miR-210 group was filled with repaired tissue while that of the control was not repaired. In gene expression analysis of the meniscus, the expression of miR-210, Collagen type 2 alpha 1 (Col2a1), Vascular endothelial growth factor (VEGF), and Fibroblast growth factor-2 (FGF2) in the miR-210 group was significantly higher than that in the control. At 12 weeks, the intra-articular injection of miR-210 had healed the injured site of the meniscus and had prevented articular cartilage degeneration. In vitro, miR-210 upregulated Col2a1 expression in the meniscus cells and VEGF and FGF2 expression in the synovial cells.ConclusionsAn intra-articular injection of ds miR-210 was effective in the healing of the damaged white zone meniscus through promotion of the collagen type 2 production from meniscus cells and through upregulated of VEGF and FGF2 from synovial cells.

MicroRNA‐210 Promotes Accumulation of Neural Precursor Cells Around Ischemic Foci After Cerebral Ischemia by Regulating the SOCS1–STAT3–VEGF‐C Pathway

“…MicroRNA acts through posttranscriptional regulation of target genes, leading to the degradation of target gene mRNAs or translational inhibition. The results from this study and previous studies showed increased VEGF and STAT3 expression when miR‐210 was overexpressed . Consequently, we hypothesized that VEGF and STAT3 may not be direct targets of miR‐210.…”

“…The findings confirmed that miR‐210 expression increased in both hypoxic brain tissue and EPCs. The overexpression of miR‐210 in endothelial cells in vitro promoted the formation of capillary‐like structures, and the local injection of miR‐210 promoted vascular proliferation in injured joints, the Achilles tendon, and the myocardium . The overexpression of miR‐210 in the striatum by local injection of lentivirus was previously shown to enhance angiogenesis in the basal ganglia and neurogenesis in the SVZ and hippocampus of both normal and cerebral ischemia mice .…”

“…VEGF and VEGF receptor (VEGFR) expression is upregulated in the ischemic penumbra, which is beneficial for neurovascular remodeling and neurological function recovery after a hypoxic/ischemic cerebral injury . Several studies indicated that miR‐210 upregulates VEGF expression . Therefore, we hypothesized that EPC homing may be involved in cerebral neovascularization following cerebral ischemia and that miR‐210 in EPCs upregulates VEGF under hypoxic conditions, promoting NPC accumulation and survival around ischemic foci and neurological function recovery.…”

The Epigenomic Landscape in Osteoarthritis

“…For example, a recent study demonstrated that intraarticular delivery of an antagonist of miR-483-5p (previously identified as overexpressed in OA chondrocytes) delayed the progression of OA in mice using the DMM post-traumatic model, specifically by modulating matrilin 3 and tissue inhibitor of metalloproteinase 2 (TIMP-2) [72]. A second study published in 2014 examined intraarticular injection of miRNA-210 in partially transected anterior cruciate ligaments of rats and found increased healing by the enhancement of angiogenesis through upregulation of VEGF and FGF2 expression, along with increases in transcription of Col2a1 [73]. Despite tissue evidence of miRNA dysregulation in OA, a very recent study in mice failed to identify a circulating serum miRNA profile associated with early OA damage [74].…”

MicroRNA-210 and its theranostic potential

“…The same technique has also produced a desired effect in accelerating avascular meniscal healing in rat medial meniscal injured model [132]. Since oligonucleotides or virus based constructs can systemically reintroduce a tumour-suppressor miRNA into cancer cells so as to repress tumour growth [133], miR-210 may be a favorable future treatment approach for ESCC patients.…”